Glioblastoma‐derived tumorospheres identify a population of tumor stem‐like cells with angiogenic potential and enhanced multidrug resistance phenotype

Abstract

We investigated in vitro the properties of selected populations of cancer stem-like cells defined as tumorospheres that were obtained from human glioblastoma. We also assessed their potential and capability of differentiating into mature cells of the central nervous system. In vivo, their tumorigenicity was confirmed after transplantation into the brain of non-obese diabetic/severe combined immunodeficient (NOD-SCID) mice. The angiogenic potential of tumorospheres and glioblastoma-derived cells grown as adherent cells was revealed by evaluating the release of angiogenic factors such as vascular endothelial growth factor and CXCL12 by ELISA, as well as by rat aortic ring assay. The proliferative response of tumorospheres in the presence of CXCL12 was observed for the first time. Multidrug resistance-associated proteins 1 and 3 as well as other molecules conferring multidrug resistance were higher when compared with primary adherent cells derived from the same tumor. Finally, we obtained cells from the tumor developing after grafting that clearly expressed the putative neural stem cell marker CD133 as shown by FACS analysis and also nestin and CXCR4. The cells' positivity for glial fibrillary acidic protein was very low. Moreover these cells preserved their angiogenic potential. We conclude that human glioblastoma could contain tumor cell subsets with angiogenic and chemoresistance properties and that this chemoresistance potential is highly preserved by immature cells whereas the angiogenic potential is, to a higher extent, a property of mature cells. A better understanding of the features of these cell subsets may favor the development of more specifically targeted therapies.

Expansion of CD133+ colon cancer cultures retaining stem cell properties to enable cancer stem cell target discovery

“…Resistance of CSC populations to therapy was first reported in human acute myeloid leukaemia CD34 þ /CD38 À stem cells (Costello et al, 2000). Since then, resistance to chemotherapy and/or radiotherapy has been linked to CSC sub-populations in various solid tumours, including glioblastoma (Bao et al, 2006;Liu et al, 2006;Salmaggi et al, 2006), breast (Phillips et al, 2006), lung (Eramo et al, 2008) and colon cancers. Consistent with previous studies, our results confirm that colon CSCs exhibit enhanced resistance to the standard chemotherapeutic agent irinotecan compared with their serum-cultured differentiated derivatives.…”

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

“…Briefly, cell intensity files were processed using the Robust Multi-Array Analysis procedure (79), an algorithm that is publicly available at the Bioconductor.org website. 5 The Robust Multi-Array Analysis method was used to convert the intensities from the multiple probes of a probe set into a single expression value with greater precision and reduced background noise (relying on the perfect match probes only and thus ignoring the mismatch probes) and then to normalize by sketch quantile normalization. Quality assessments were also done in the expression console environment.…”

“…The term "tumor initiating cells" (TIC) is frequently used to describe such cells (4), and we shall use it throughout this article to indicate cells with cancer stem cell capacity. Due to the fact that TICs promote the tumor chemoresistance (5,6), radioresistance (3,7), and angiogenesis (5,8), it is conceivable that finding a manner to kill them would improve GBM therapy (9,10).…”

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

“…Current barriers to successful treatment include their complex tumor heterogeneity, diffuse invasiveness, and the presence of a subpopulation of glioma cells with stem-like properties, herein termed brain tumor-initiating cells (BTIC; refs. 2,3), that have been shown to confer resistance to conventional therapies, such as radio-and chemotherapies (4)(5)(6)(7)(8). Thus, to improve clinical outcomes, therapeutic agents should target both the infiltrative and tumor-initiating disease reservoirs.…”